Abstract
To examine further the genetic determinants of cholesterol gallstone susceptibility in inbred mice, we performed quantitative trait locus (QTL) analysis of an intercross of gallstone-susceptible PERA/EiJ and gallstone-resistant DBA/2J inbred mice. Three hundred twenty-four F2 offspring were phenotyped for cholelithiasis during consumption of a lithogenic diet and genotyped using microsatellite markers. Linkage analysis was performed by interval mapping. In addition, we analyzed the combined datasets from this cross and from an independent cross of strain PERA and gallstone-resistant I/Ln mice. QTL mapping detected one significant new gallstone susceptibility (Lith) locus on Chromosome 13 (Lith15). A second significant QTL on Chr 6 (Lith16) confirmed a previous QTL. Furthermore, suggestive QTLs confirmed Lith loci from previous crosses on Chromosomes 1, 2, 5, 16 and X. QTL analysis of the dataset derived from the combined crosses increased the detection power and narrowed confidence intervals of Lith loci on Chromosomes 2, 6, 13, and 16. Moreover, the analysis of combined datasets revealed a shared QTL between both crosses on Chromosome 17 (Lith9). Significantly higher mRNA expression of Abcg5 and Abcg8 in strain PERA compared with strains I/Ln and DBA/2 further substantiated that the PERA allele of Abcg5/Abcg8 was responsible for lithogenicity underlying Lith9.
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Acknowledgments
The study was supported by grants DK 51568 (to B.P.), DK 36588, DK 52911, and DK 34854 (to M.C.C), and GM 70683 (to GAC). H.W. (WI 1905/1-1) was supported by the Deutsche Forschungsgemeinschaft. M.A.L. was supported by the American Physiological Society, the American Liver Foundation, and the National Health and Medical Research Council of Australia (222913). The authors thank Harry Whitmore for colony management, Monika Leonard for technical advice, and David Higgins for technical assistance.
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Wittenburg, H., Lyons, M.A., Li, R. et al. Association of a lithogenic Abcg5/Abcg8 allele on Chromosome 17 (Lith9) with cholesterol gallstone formation in PERA/EiJ mice. Mamm Genome 16, 495–504 (2005). https://doi.org/10.1007/s00335-005-0006-2
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DOI: https://doi.org/10.1007/s00335-005-0006-2